Project Summary/Abstract Mitochondrial dysfunction causes mitochondrial diseases and is tightly linked to aging and neurodegenerative disorders such as Parkinson's and Alzheimer's. Recent discoveries support that mitochondrial dysfunction can be overcome to treat age-related decline. CyteGen's hypothesis is that exercise induces the secretion of blood- borne proteins that act systemically to stimulate removal of damaged mitochondria and enrichment of healthy mitochondria (mitochondrial fitness). The company's goal is to identify these proteins to develop into biologics that would serve as a platform to treat the myriad of diseases associated with mitochondrial dysfunction. The discovery platform builds on existing work that exercise reversed mitochondrial dysfunction in a mouse model for mitochondrial disease. In this application, the candidate factors are tested in a cell-based mitochondrial respiration assay in Aim 1 and evaluated known agonists of mitochondrial biogenesis [bezafibrate and the glitazones (PPAR agonists); metformin and AICAR (AMPK); and resveratrol (Sirt1)]. The results will be a rank ordering of each candidate factor based on their ability to improve respiration. In Aim 2, false positives will be eliminated through commonplace assays to assess mitochondrial morphological analyses, mtDNA copy number, and expression of mitochondrial quality control proteins. These data will winnow the list to a lead biologic candidate for Phase II development in pre-clinical models and translation into clinical trials.